CN101203517A - 1- ( 2-amino-3- (substituted alkyl)-3h-benzimidazoiylmethyl) -3-subtituted-1,3-dihydro-benzoimidazol-2-ones with activity on respiratory syncytial virus - Google Patents
1- ( 2-amino-3- (substituted alkyl)-3h-benzimidazoiylmethyl) -3-subtituted-1,3-dihydro-benzoimidazol-2-ones with activity on respiratory syncytial virus Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
Inhibitors of RSV replication of formula (I) which can be represented by formula (I) the salts and stereochemically isomeric forms thereof, wherein R is a radical of formula (a) or (b); Q is hydrogen or C1-6alkyl optionally substituted with a heterocycle or Q is C1-6alkyl substituted with both a radical -OR<4> and a heterocycle; Alk is C1-6alkanediyl; X is O or S; -a<1>=a<2>-a<3>=a<4> - is -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- or -CH=CH-CH=N-; R<1> is Ar or a heterocycle; R<2> is hydrogen, C1-6alkyl, substituted C1-6alkyl, C3-7cycloalkyl; R<3> is hydrogen, C1-6alkyl, cyano, aminocarbonyl, polyhaloC1-6alkyl, C2-6alkenyl or C2-6alkynyl; R<4> is hydrogen or C1-6alkyl; Ar is phenyl or substituted phenyl; Het is a heterocycle; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I).
Description
The present invention relates to respiratory syncytial virus (RSV) duplicated to have suppress active 1-[[2-amino-3-(substituted alkyl)-3H-benzimidazolyl-] methyl]-3-replaces-1,3-dihydro-benzimidazolyl-2 radicals-ketone and analog.The invention further relates to and contain these compounds as composition of active components and prepare these compounds and method for compositions.
Human RSV or respiratory syncytial virus are the big RNA viruses of a class, are the members of Paramyxoviridae, constitute the subfamily Pneumovirinae with ox RSV virus.Human RSV is the reason that causes the various respiratory tract diseases of people of all age levels of the whole world.RSV be popular in the age less than among two years old the children and be infancy and the Childhood lower respiratory illness main pathogenic factor.The baby who surpasses half meets with RSV in 1 year of their life, and nearly allly in the first two years of their life all can meet with RSV.Infection of children can cause the injury of lung that lasts for several years and may produce chronic lung disease (chronic pant, asthma), particularly chronic obstructive pulmonary disease (COPD) afterwards childhood.Bigger children and adult suffer from (bad) common cold that is caused by rsv infection through regular meeting.In the elderly, susceptibility improves once more, and RSV interrelates with the outburst of multiple old pneumonia, causes significant lethality rate.Additionally, RSV may cause immunodeficiency or immunosuppressant people, and particularly the bone marrow transplantation patient produces serious disease.
The infection that is produced by the virus of given subgroup can not prevent the follow-up infection of the RSV isolate of identical subgroup in winter subsequently.Thus, although only have two kinds of hypotype A and B, the infection again that is caused by RSV is general.
Only there are three kinds of medicines to be approved for anti-rsv infection now.First kind is ribavirin, and it is a kind of nucleoside analog, provides the aerosol treatment to the serious rsv infection of hospitalized child.The effectiveness of aerosol drug delivery approach, toxicity (teratogenic hazard), cost and height change has limited its use.Other two kinds of medicines, RespiGam_ and palivizumab, i.e. polyclone and monoclonal antibody immunity stimulant are determined and are used for prevention approach.
Up to now, the trial of other development safety and effective RSV vaccine is all failed.The vaccine of inactivation can not preventing disease, and has in fact increased the weight of disease subsequently between period of infection in some cases.Biological attenuated vaccine is attempted, but has only obtained limited success.Obviously, the current effective nontoxic and medicine that is easy to administration that needs antagonism RSV to duplicate.
Multiple benzoglyoxaline and imidazopyridine derivatives are described among WO-01/00611, WO-01/00612 and the WO-01/00615 as the RSV replication inhibitors.WO-01/95910 discloses the imidazopyridine and the imidazopyrimidine that can be used for the treatment of rsv infection.The compounds of this invention all is being different from these prior art compounds aspect chemical structure and the activity profile.
The present invention relates to the RSV replication inhibitors, it can be represented by formula (I)
Its salt and stereochemistry heterogeneous forms, wherein R is the group of following formula
Q is hydrogen or optional heterocyclically substituted C
1-6Alkyl, perhaps Q is by group-OR
4C with heterocyclic substituted
1-6Alkyl; Wherein said heterocycle is selected from _ azoles alkane, thiazolidine, 1-oxo-thiazolidine, 1,1-dioxo thiazolidine, morpholinyl, thio-morpholinyl, 1-oxo-thio-morpholinyl, 1, the assorted azepine of 1-dioxo thio-morpholinyl, six hydrogen-oxygens _ (hexahydrooxazepine), six hydrogen thia azepines _ (hexahydrothiazepine), 1-oxo-six hydrogen thia azepine _, 1,1-dioxo-six hydrogen thia azepine _, tetramethyleneimine, piperidines, high piperidines, piperazine; Wherein said heterocycle can be chosen wantonly separately by one or two and be selected from following substituting group replacement: C
1-6Alkyl, hydroxyl C
1-6Alkyl, aminocarboxyl C
1-6Alkyl, hydroxyl, carboxyl, C
1-6Alkoxy carbonyl, aminocarboxyl, list or two (C
1-6Alkyl) aminocarboxyl, C
1-6Alkyl-carbonyl-amino, amino-sulfonyl and single or two (C
1-6Alkyl) amino-sulfonyl;
Alk is C
1-6Alkylidene group;
X is O or S;
-a
1=a
2-a
3=a
4-be formula-N=CH-CH=CH-,-CH=N-CH=CH-,-CH=CH-N=CH-or-divalent group of CH=CH-CH=N-; One of them nitrogen-atoms has the chemical bond of linking group (b) and molecule remainder;
R
1For Ar or be selected from following heterocycle: pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, tetrahydrofuran base, thienyl, pyrryl, thiazolyl, _ azoles base, imidazolyl, isothiazolyl, pyrazolyl, different _ the azoles base, _ di azoly, quinolyl, quinoxalinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo _ azoles base, benzothiazolyl, the pyridopyridine base, naphthyridinyl, 1H-imidazo [4,5-b] pyridyl, 3H-imidazo [4,5-b] pyridyl, imidazo [1,2-a] pyridyl and 2,3-dihydro-1,4-two _ alkene is (dioxino) [2,3-b] pyridyl also; Wherein each described heterocycle can be chosen wantonly by 1,2 or 3 and be selected from following substituting group replacement independently of one another: halogen, hydroxyl, amino, cyano group, carboxyl, C
1-6Alkyl, C
1-6Alkoxyl group, hydroxyl C
1-6Alkoxyl group, (C
1-6Alkyl-oxygen base) C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkoxy C
1-6Alkyl, hydroxyl C
1-6Alkyl, list or two (C
1-6Alkyl) amino, single or two (C
1-6Alkyl) amino C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6Alkyl-carbonyl-amino, C
1-6Alkoxy carbonyl, aminocarboxyl, list and two-C
1-6Alkyl amino-carbonyl;
R
2Be hydrogen, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, Ar-C
1-6Alkoxy C
1-6Alkyl, C
3-7Cycloalkyl, cyano group-C
1-6Alkyl, Ar-C
1-6Alkyl, Het-C
1-6Alkyl;
R
3Be hydrogen, C
1-6Alkyl, cyano group, aminocarboxyl, many halos C
1-6Alkyl, C
2-6Thiazolinyl or C
2-6Alkynyl;
R
4Be hydrogen or C
1-6Alkyl;
Ar is phenyl or by 1～5 independently of one another, is selected from the phenyl that following substituting group replaces such as 1,2,3 or 4: halogen, hydroxyl, amino, list or two (C
1-6Alkyl) amino, C
1-6Alkyl-carbonyl-amino, C
1-6Alkyl sulfonyl-amino, cyano group, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, phenyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, amino C
1-6Alkyl, list or two (C
1-6Alkyl) amino C
1-6Alkyl, C
1-6Alkoxyl group, many halos C
1-6Alkoxyl group, phenoxy group, aminocarboxyl, list or two (C
1-6Alkyl) aminocarboxyl, hydroxycarbonyl group, C
1-6Alkoxy carbonyl, C
1-6Alkyl-carbonyl, amino-sulfonyl, list and two (C
1-6Alkyl) amino-sulfonyl;
Het is selected from following heterocycle: pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, tetrahydrofuran base, thienyl, pyrryl, thiazolyl, _ azoles base, imidazolyl, isothiazolyl, pyrazolyl, different _ the azoles base, _ di azoly, quinolyl, quinoxalinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo _ azoles base, benzothiazolyl, the pyridopyridine base, naphthyridinyl, 1H-imidazo [4,5-b] pyridyl, 3H-imidazo [4,5-b] pyridyl, imidazo [1,2-a] pyridyl and 2,3-dihydro-1,4-two _ alkene is [2,3-b] pyridyl also; Wherein Het can choose wantonly separately by 1,2 or 3 and be selected from halogen, hydroxyl, amino, list or two (C independently of one another
1-6Alkyl) amino, cyano group, C
1-6Alkyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6The substituting group of alkoxyl group replaces.
Group (a) and (b) in dotted line represent with (a) or (b) to be connected key on the molecule remainder.In group (b), this key is connected a
1=a
2-a
3=a
4In a nitrogen-atoms on, thereby described nitrogen-atoms has positive charge (pyridine _ positively charged ion).
The invention still further relates to formula (I) compound or its additive salt or stereochemistry heterogeneous forms and be used to make the purposes that suppresses the medicine that RSV duplicates.Perhaps, the present invention relates to suppress the method that RSV duplicates in the warm-blooded animal, described method comprises formula (I) compound, its additive salt or the stereochemistry heterogeneous forms of effective dosage.
As above hereinafter use, as the part of group or group (for example at many halos C
1-6In the alkoxyl group) " many halos C of using
1-6Alkyl " be defined as the C that single or many halogen replaces
1-6Alkyl is particularly by maximum 1,2,3,4,5,6 or the C that replaces of more a plurality of halogen atom
1-6Alkyl, such as methyl that is replaced by one or more fluorine atom or ethyl, for example, difluoromethyl, trifluoromethyl, trifluoroethyl.Preferred trifluoromethyl.Also comprise perfluoro C
1-6Alkyl, this group are the C that all replaced by fluorine atom of all hydrogen atoms wherein
1-6Alkyl, for example pentafluoroethyl group.At many halos C
1-4In the definition of alkyl, in the situation that is connected more than a halogen atom on the alkyl, described halogen atom can be identical or different.
Each Ar can be unsubstituted phenyl or the phenyl that replaced by 1～5 substituting group, such as 5 or 4 substituting groups, and preferred maximum 3 substituting groups, perhaps maximum two substituting groups are perhaps replaced by a substituting group.
When on Sauerstoffatom or nitrogen-atoms, replacing, preferred hydroxyl C
1-6Alkyl is hydroxyl C
2-6Alkyl, wherein hydroxyl and oxygen or nitrogen-atoms are by at least two carbon atoms separate.
At this " C that uses as the part of group or group
1-4Alkyl " be defined as straight chain or branched saturated hydrocarbon group with 1～4 carbon atom, such as, for example be methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl isophthalic acid-propyl group; " C
1-6Alkyl " comprise C
1-4Alkyl and its have the higher homologue of 5 or 6 carbon atoms, such as, for example be 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl, 2-methyl-1-butene base, 2-methyl-1-pentene base, 2-ethyl-1-butyl, 3-methyl-2-amyl group or the like.Wherein preferred C
1-6Alkyl is C
1-4Alkyl.
Term " the C that uses as the part of group or group
2-6Thiazolinyl " be defined as the straight chain and the branched hydrocarbyl that have the two keys of saturated C-C and at least one and have 2～6 carbon atoms; such as, for example be vinyl, 1-propenyl, 2-propenyl (perhaps allyl group), 1-butylene base, crotyl, 3-butenyl, 2-methyl-2-propenyl, pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butene base, 2-methyl-pentenyl or the like.Preferred C
2-6Thiazolinyl is C
2-4Thiazolinyl.
Term " C as the part of group or group
2-6Alkynyl " be defined as the straight chain and the branched hydrocarbyl that have saturated C-C and at least one triple bond and have 2～6 carbon atoms; such as, for example be ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, valerylene base, 3-pentynyl, 2-hexin base, 3-hexin base or the like.Preferred C
2-6Alkynyl is C
2-4Alkynyl.
C
3-7Cycloalkyl is meant the upperseat concept of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
C
1-6Alkylidene group is defined as straight chain and the branched saturated hydrocarbon group with 1～6 carbon atom, such as, for example be methylene radical, ethylidene, trimethylene, tetramethylene, propylene, 2,3-butylidene, pentamethylene, hexamethylene or the like.Wherein preferred C
1-6Alkylidene group is C
1-4Alkylidene group.
As previous application, in the time of on being connected carbon atom, term (=O) form carbonyl moiety, in the time of on being connected sulphur atom, form the sulfoxide part and when two described terms are connected on the sulphur atom, formation alkylsulfonyl part.
Term " halogen " is meant the upperseat concept of fluorine, chlorine, bromine and iodine.
Should be pointed out that the group position on any molecular moiety that uses can be the optional position on the described part in definition, as long as its chemical property is stable.
Except as otherwise noted, the group that uses in variable-definition comprises its all possible isomer.For example, pyridyl comprises 2-pyridyl, 3-pyridyl and 4-pyridyl; Amyl group comprises 1-amyl group, 2-amyl group and 3-amyl group.
When any variable existed more than one time on any structure, its each time definition was independently.
Some formulas (I) compound can contain one or more chiral centre and exist with stereochemistry heterogeneous forms.As used herein term " stereochemistry heterogeneous forms " be defined as formula (I) but compound can have all form institute by identical carbon atoms in proper order by identical keyed jointing with three-dimensional structure that difference can not change mutually might compound.
Unless otherwise mentioned or show, the chemical name of compound comprise that described compound can have might stereochemistry heterogeneous forms mixture.Described mixture can contain all diastereomers and/or the enantiomer of the described compound of basic molecular structure.All stereochemistry heterogeneous forms of The compounds of this invention (pure form or mutual blended form) all are intended to be included within the scope of the invention.
As the pure stereoisomeric forms in any ratio of the compound put down in writing herein and intermediate be defined as be substantially free of identical basic molecular structure as described in compound or other enantiomerism of intermediate or the isomer of diastereo-isomerism form.Particularly, term " stereoisomerism is pure " is meant stereoisomerism excessive at least 80% (promptly, a kind of isomer is minimum be 90% and another kind of possible isomer be up to 10%) as many as stereoisomerism excessive 100% (promptly, a kind of isomer is 100% and does not have other isomer) compound or intermediate, more especially, the compound or the intermediate of stereoisomerism excessive 90% as many as 100%, stereoisomerism excessive 94% as many as 100% more especially, and stereoisomerism excessive 97% as many as 100% the most particularly.Term " enantiomer-pure " and " diastereo-isomerism is pure " should be understood in a similar fashion, but should be noted that this moment enantiomerism excessive be respectively that the diastereo-isomerism of described mixture is excessive.
The pure stereoisomeric forms in any ratio of The compounds of this invention and intermediate can obtain preparation by using methods known in the art.For example, enantiomer can be by obtaining separated from one another with optically active acid or their non-mapping salt of alkali selective freezing.The example is tartrate, dibenzoyl tartaric acid, dimethylbenzene acyl group tartrate and norcamphane sulfonic acid.Additionally, enantiomer can be separated by the chromatographic technique that utilizes chiral stationary phase.Described pure stereochemistry heterogeneous forms can also be derived by the suitable raw material of corresponding pure stereochemistry heterogeneous forms and be obtained, and condition is that described reaction exists stereospecificity.If expectation obtains concrete steric isomer, so described compound synthesizes by stereospecific preparation method.To the advantageously pure raw material of applied optics isomery in these methods.
The diastereomer racemoid of formula (I) can be prepared separately by ordinary method.The suitable physical separation method that can advantageously use is, for example selective freezing and chromatography, for example column chromatography.
For the intermediate of some formulas (I) compound and use in its preparation, its absolute stereo chemical structure does not need test to determine.Those skilled in the art can utilize methods known in the art to determine the absolute configuration of described compound, such as, for example be X-ray diffraction.
The present invention also is intended to comprise all isotropic substance forms of the atom that is present on the The compounds of this invention.Isotropic substance comprises that those have the atom of same atoms ordinal sum different mass number.Usually, such as but not limited to, the isotropic substance of hydrogen comprises tritium and deuterium.The isotropic substance of carbon comprises C-13 and C-14.
Term " formula (I) compound " or any similar term such as " The compounds of this invention " or the like, also mean any prodrug that comprises that formula (I) compound may form.Term " prodrug " comprises acceptable derivates on any pharmacology as used herein, such as ester, acid amides and phosphoric acid salt, thereby makes that the interior bio-transformation product of body of described derivative is suc as formula defined active medicine in (I) compound.The Goodman of general description prodrug and Gilman (The PharmacologicalBasis of Therapeutics, 8th ed, McGraw-Hill, Int.Ed.1992, " Biotransformation of Drugs ", p13 15) reference be hereby incorporated by.Preferred prodrug have good water-soluble, the bioavailability that raises and can be in vivo easily metabolism be activity inhibitor.The prodrug of The compounds of this invention can obtain preparation by modifying the functional group be present in the compound in a certain way, thereby by routine operation or make described modifier be cracked into parent compound in vivo.
Preferably hydrolysis and the pharmaceutically acceptable ester prodrugs that obtains by those formula (I) compound derivings in vivo with hydroxyl or carboxyl.The ester of hydrolysis is for being hydrolyzed into the ester of parent acid or alcohol in the mankind or animal body in vivo.The suitable pharmaceutically acceptable ester of carboxyl comprises can be formed on the C on any carboxyl in the The compounds of this invention
1-6Alkoxy methyl ester (for example methoxymethyl ester), C
1-6Alkanoyloxymethyl ester (for example oxy acid methyl neopentyl ester), phthalidyl ester, C
3-7Cyclo alkoxy carbonyl oxygen base C
1-6Alkyl ester (for example 1-cyclohexyl-carbonyl oxygen base ethyl ester), 1,3-dioxolen-2-ketone group methyl ester (for example 5-methyl isophthalic acid, 3-dioxolen-2-ketone group methyl ester) and C
1-6Alkoxy-carbonyl oxy ethyl ester (for example 1-methoxycarbonyl oxygen base ethyl ester).
Contain in the body of formula (I) compound of hydroxyl hydrolyzable ester and comprise inorganic ester (such as, phosphoric acid ester) and alpha-acyloxy alkyl oxide and because the interior hydrolysis of the body of ester and cracking obtains the related compound of parent hydroxy.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxy-ether.The selection of hydrolyzable ester formation group comprises benzoyl and phenylacetyl, alkoxy carbonyl (to obtain alkyl carbonate), dialkyl amido formyl radical and N-(dialkyl amido ethyl)-N-alkyl-carbamoyl (to obtain carbamate), dialkyl amido ethanoyl and the carboxyl ethanoyl of alkyloyl, benzoyl, phenylacetyl and replacement in the body of hydroxyl.Substituent example on the benzoyl comprises from theheterocyclic nitrogen atom and is connected morpholino and piperidino-(1-position only) on benzoyl basic ring 3-or the 4-position through methylene group.The alkyloyl ester for example is any C
1-30Alkyloyl ester, particularly C
8-30Alkyloyl ester, more especially C
10-24Alkyloyl ester, further C particularly
16-20The alkyloyl ester, wherein moieties can have one or more pair key.The example of alkyloyl ester is decylate, cetylate and stearate.
Term " formula (I) compound " or any similar term such as " The compounds of this invention " or the like, also mean and comprise any metabolite that forms in vivo by the administration of medicine.Some examples according to metabolite of the present invention include but not limited to that (a) its Chinese style (I) compound contains methyl, its hydroxymethyl derivative; (b) wherein (I) compound contains alkoxyl group, its hydroxy derivatives; (c) its Chinese style (I) compound contains uncle's amino, its secondary amino group derivative; (d) its Chinese style (I) compound contains secondary amino group, its primary amino derivative; (e) its Chinese style (I) compound contains phenyl moiety, its phenol derivatives; (f) its Chinese style (I) compound contains amide group, its carboxylic acid derivative.
Term " formula (I) compound " or any similar term, such as " The compounds of this invention " or the like, also mean any N-oxide form that comprises formula (I) compound, it is formula (I) compound that one or several nitrogen-atoms are oxidized to the N-oxide form.
Term " formula (I) compound " or any similar term, such as " The compounds of this invention " or the like, also mean and comprise quaternary amine, it is the quaternary ammonium salt that basic nitrogen that formula (I) compound can through type (I) compound and suitable quaternizing agent reaction form, described quaternizing agent such as, for example be optional alkyl halide, aryl halide or the arylalkyl halogenide that replaces, for example methyl iodide or benzyl iodide.Can also use other reactant with good leavings group, such as alkyl triflate, alkyl methanesulfonates and alkyl right-tosylate.Quaternary amines has positively charged nitrogen.Pharmaceutically acceptable gegenion comprises chlorine, bromine, iodine, trifluoroacetate and acetate.The gegenion of selecting can be introduced by making spent ion exchange resin.
Term " formula (I) compound " or any similar term, such as " The compounds of this invention " or the like, also mean the metal complexes or the inner complex that comprise formula (I) compound, wherein title complex or inner complex are metal complexes or the inner complexs that is formed by acceptable metal ion on the physiology, and described metal ion is Ca, Zn, Mg or Fe ion for example.The metal complexes of described formula (I) compound or inner complex derivative can obtain preparation by making formula (I) compound and reacting metal salt.
For therapeutic applications, the salt of formula (I) compound is that wherein gegenion is those salt of pharmaceutically acceptable gegenion.Yet the salt of non-pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry can also be used for, for example in preparation or the pharmaceutically acceptable compound of purifying.All salt is no matter be that pharmacy acceptable salt or non-pharmaceutically acceptable salt all are included within the scope of the invention.
The pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry additive salt of being put down in writing as mentioned means the non-toxic acid and the base addition salt form of the therapeutic activity that comprises that formula (I) compound can form.Pharmaceutically-acceptable acid addition can be easily by obtaining preparation with described suitable acid treatment alkali form.Suitable acid comprises that for example, mineral acid is such as haloid acid (for example spirit of salt or Hydrogen bromide), sulfuric acid, nitric acid, phosphoric acid or the like; Perhaps organic acid, such as, be acetate, propionic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid (being oxalic acid), propanedioic acid, succsinic acid (being Succinic Acid), toxilic acid, fumaric acid, oxysuccinic acid (being hydroxy-butanedioic acid), tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexane sulfamic acid, Whitfield's ointment, para-aminosalicylic acid for example, pounce on acid (pamoic) or the like.
On the contrary, by with suitable alkaline purification, above-mentioned salt form can be converted into free alkali form.
By handling with suitable organic and mineral alkali, formula (I) compound that contains acid proton can also be converted into their no noxious metals or amine additive salt form.Suitable base salt forms comprises, for example, ammonium salt, basic metal and alkaline earth salt (for example lithium, sodium, potassium, magnesium and calcium salt or the like), salt with organic bases formation, for example this is first given birth to (benzathine), N-methyl D-glycosamine, breathes out amine (hydrabamine) salt, with with amino acids formed salt, such as, for example arginine and Methionin or the like.
Applied term " additive salt " also comprises the solvate that formula (I) compound and salt thereof can form as mentioned.Described solvate for example is hydrate and alcoholate or the like.
Some formulas (I) compound can also exist with their tautomeric form.Though offered some clarification in following formula, intention is included in the scope of the present invention this form.
Embodiment of the present invention relate to formula (I-a) or (I-b) compound:
Further embodiment of the present invention relates to formula (I-a-1) or (I-a-2) compound:
At (I-a), (I-b), (I-a-1) with (I-a-2), Q, R, Alk, X, R
1, R
2, R
3Suc as formula (I) compound or anyly in the definition of this formula that offers some clarification on (I) compound subgroup, offer some clarification on.
Should be appreciated that formula (I-a), (I-b), (I-a-1) of above-mentioned definition, subgroup and any other subgroup of definition in this article of (I-b-1) compound also mean any additive salt and the stereochemistry heterogeneous forms that comprises described compound.
Hereinafter, the multiple subgroup of formula (I) compound is by the restriction defined declaration of the multiple group in formula (I) compound.Yet these subgroups also are intended to comprise any displacement of the restriction definition of hereinafter record.
The subgroup I of formula (I) compound is any subgroup of those compounds of formula (I) or formula (I) compound that describes in detail herein, and wherein Alk is ethylidene or methylene radical, and more especially wherein Alk is a methylene radical.
The subgroup II of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, wherein
(a) R
1For Ar or be selected from following heterocycle: pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, thienyl, pyrryl, thiazolyl, _ azoles base, imidazolyl, isothiazolyl, pyrazolyl, different _ the azoles base, quinolyl, benzofuryl, benzimidazolyl-, benzo _ azoles base, benzothiazolyl; Wherein each described heterocycle can be chosen wantonly by 1,2 or 3 and be selected from following substituting group replacement independently of one another: halogen, hydroxyl, amino, cyano group, carboxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkoxy C
1-6Alkyl, hydroxyl C
1-6Alkyl, list or two (C
1-6Alkyl) amino, single or two (C
1-6Alkyl) amino C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6Alkoxy carbonyl, aminocarboxyl, list and two C
1-6Alkyl amino-carbonyl;
(b) R
1For Ar or be selected from the heterocycle of quinolyl, benzimidazolyl-, pyrazinyl or pyridyl; Wherein each described heterocycle can be chosen wantonly by 1,2 or 3 and be selected from following substituting group replacement independently of one another: halogen, hydroxyl, amino, cyano group, carboxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, hydroxyl C
1-6Alkyl, list or two (C
1-6Alkyl) amino, single or two (C
1-6Alkyl) amino C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6Alkoxy carbonyl, aminocarboxyl, list and two C
1-6Alkyl amino-carbonyl;
(c) R
1Be Ar, quinolyl, benzimidazolyl-, pyrazinyl or pyridyl, wherein these groups can be chosen wantonly separately by one, two or three and be selected from halogen, hydroxyl, C
1-6Alkyl, C
1-6The group of alkoxyl group replaces;
(d) R
1Be selected from halogen, hydroxyl, C for optional by one, two or three
1-6Alkyl, C
1-6The phenyl that the group of alkoxyl group replaces; Quinolyl; Optional by C
1-6The benzimidazolyl-that alkyl replaces; Choose wantonly and be selected from hydroxyl, halogen, C by one or two
1-6Alkyl, benzyloxy and C
1-6The pyridyl that the group of alkoxyl group replaces; Choose wantonly and be selected from C by maximum three
1-6The pyrazinyl that the group of alkyl replaces; Perhaps be substituted or choose wantonly the pyridyl of replacement as institute's detaileds description in above (a)-(i);
(e) R
1Be selected from halogen, hydroxyl, C for optional by one or two
1-6Alkyl, C
1-6The phenyl that the group of alkoxyl group replaces;
(f) R
1Be selected from C for optional by maximum three
1-6The pyrazinyl that the group of alkyl replaces;
(g) R
1For being independently selected from hydroxyl, C by 1 or 2
1-6Alkyl, halogen, C
1-6Alkoxyl group and (C
1-6Alkoxyl group) C
1-6The pyridyl that the substituting group of alkoxyl group replaces;
(h) R
1For being independently selected from hydroxyl, C by 1 or 2
1-6Alkyl, halogen and C
1-6The pyridyl that the substituting group of alkoxyl group replaces;
(i) R
1For being independently selected from hydroxyl and C by 1 or 2
1-6The pyridyl that the substituting group of alkyl replaces;
(j) R
1For by hydroxyl and C
1-6The pyridyl that alkyl replaces.
Embodiment of the present invention are methylene radical and R for Alk wherein
1As formula (I) compound that described in detail in above (a)-(j) or any subgroup of formula (I) compound.
The subgroup III of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I and II, wherein
(a) R
2Be hydrogen, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, Ar-C
1-6Alkoxy C
1-6Alkyl, C
3-7Cycloalkyl, cyano group-C
1-6Alkyl, Ar-C
1-6Alkyl;
(b) R
2Be C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, Ar-C
1-6Alkoxy C
1-6Alkyl, C
3-7Cycloalkyl, cyano group-C
1-6Alkyl, Ar-C
1-6Alkyl;
(c) R
2Be hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, Ar-C
1-6Alkoxy C
1-6Alkyl, C
3-7Cycloalkyl;
(d) R
2Be C
3-7Cycloalkyl;
(e) R
2Be cyclopropyl.
The subgroup IV of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, II and III, wherein
(a) Het be pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, tetrahydrofuran base, thienyl, pyrryl, thiazolyl, _ azoles base, imidazolyl, isothiazolyl, pyrazolyl, different _ the azoles base, _ di azoly, quinolyl, quinoxalinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo _ azoles base, benzothiazolyl; Wherein Het can choose wantonly separately by 1,2 or 3 and be selected from halogen, hydroxyl, amino, list or two (C independently of one another
1-4Alkyl) amino, cyano group, C
1-6Alkyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6The substituting group of alkoxyl group replaces;
(b) Het be pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, tetrahydrofuran base, thienyl, pyrryl, thiazolyl, _ azoles base, imidazolyl, isothiazolyl, pyrazolyl, different _ the azoles base, _ di azoly, quinolyl, quinoxalinyl; Wherein Het can choose wantonly separately by 1,2 or 3 and be selected from halogen, hydroxyl, amino, list or two (C independently of one another
1-4Alkyl) amino, cyano group, C
1-6Alkyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6The substituting group of alkoxyl group replaces;
(c) Het be pyridyl, pyrazinyl, pyrimidyl, furyl, thienyl, thiazolyl, _ azoles base, imidazolyl; Wherein Het can choose wantonly separately by 1,2 or 3 and be selected from halogen, hydroxyl, amino, list or two (C independently of one another
1-4Alkyl) amino, cyano group, C
1-6Alkyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6The substituting group of alkoxyl group replaces;
(d) Het be pyridyl, pyrazinyl, pyrimidyl, furyl, thienyl, thiazolyl, _ azoles base, imidazolyl; Wherein Het can choose wantonly separately by 1,2 or 3 and be selected from halogen, hydroxyl, amino, list or two (C independently of one another
1-4Alkyl) amino, cyano group, C
1-6Alkyl, C
1-6The substituting group of alkoxyl group replaces; Perhaps
(e) Het be selected from pyridyl, pyrazinyl, pyrimidyl, furyl, thienyl, thiazolyl, _ heterocycle of azoles base, imidazolyl.
The subgroup V of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, II, III and IV, wherein
(a) R
3Be hydrogen, C
1-6Alkyl, cyano group, aminocarboxyl; Perhaps (b) R
3Be hydrogen.
The subgroup VI of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, II, III, IV and V, wherein R
4Be hydrogen.
The subgroup VII of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, II, III, IV, V and VI, wherein-a
1=a
2-a
3=a
4-be formula-CH=CH-CH=CH-,-CH=N-CH=CH-or-divalent group of CH=CH-N=CH-; Perhaps wherein-a
1=a
2-a
3=a
4-be formula-CH=CH-CH=CH-or-divalent group of CH=N-CH=CH-.
The subgroup VIII of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, II, III, IV, V, VI and VII, wherein
(a) Q is hydrogen or optional heterocyclically substituted C
1-6Alkyl, perhaps Q is by group-OR
4C with heterocyclic substituted
1-6Alkyl; Wherein said heterocycle is selected from _ azoles alkane, thiazolidine, 1-oxo-thiazolidine, 1,1-dioxo thiazolidine, morpholinyl, thio-morpholinyl, 1-oxo-thio-morpholinyl, 1, the assorted azepine of 1-dioxo thio-morpholinyl, six hydrogen-oxygens _, six hydrogen thia azepines _, 1-oxo-six hydrogen thia azepine _, 1,1-dioxo-six hydrogen thia azepine _; Wherein said heterocycle can be chosen wantonly separately and is selected from C by one or two
1-6Alkyl, hydroxyl C
1-6Alkyl, hydroxyl, carboxyl, C
1-6Alkoxy carbonyl, aminocarboxy substituting group replace; Perhaps
(b) Q is hydrogen or optional heterocyclically substituted C
1-6Alkyl, perhaps Q is by group-OR
4C with heterocyclic substituted
1-6Alkyl; Wherein said heterocycle is selected from _ azoles alkane, thiazolidine, 1-oxo-thiazolidine, 1, and 1-dioxo thiazolidine, morpholinyl, thio-morpholinyl, 1-oxo-thio-morpholinyl, 1,1-dioxo thio-morpholinyl; Wherein said heterocycle can be chosen wantonly separately and is selected from C by one or two
1-6Alkyl, hydroxyl C
1-6The substituting group of alkyl, hydroxyl replaces; Perhaps
(c) Q is hydrogen or optional heterocyclically substituted C
1-6Alkyl, perhaps Q is by group-OR
4C with heterocyclic substituted
1-6Alkyl; Wherein said heterocycle is selected from _ azoles alkane, thiazolidine, morpholinyl, thio-morpholinyl; Wherein said heterocycle can be chosen wantonly by one or two C separately
1-6Alkyl group replaces; Perhaps
(d) Q is by the C of morpholinyl or thio-morpholinyl replacement
1-6Alkyl.
In (a)-(d) of last paragraph, heterocycle, such as _ azoles alkane, thiazolidine, 1-oxo-thiazolidine, 1,1-dioxo thiazolidine, morpholinyl, thio-morpholinyl or the like, preferably the nitrogen-atoms by them is connected the C that their replace
1-6On the alkyl.
The subgroup IX of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, II, III, IV, V, VI, VII and VIII, wherein one or more Ar are phenyl or by 1,2,3 or the phenyl that replaced by those substituting groups of mentioning in 1,2 definition that is selected from formula (I) compound or its any subgroup.
The subgroup X of formula (I) compound is any subgroup of following those formulas (I) compound or formula (I) compound that describes in detail herein, such as above-mentioned subgroup I, II, III, IV, V, VI, VII, VIII and IX, wherein
(a) one or more Ar are phenyl or by maximum 3, perhaps by maximum 2, perhaps are selected from the phenyl that following substituting group replaces by 1: halogen, hydroxyl, amino, cyano group, C
1-6Alkyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, amino C
1-6Alkyl, C
1-6Alkoxyl group, amino-sulfonyl, aminocarboxyl, hydroxycarbonyl group, C
1-4Alkyl-carbonyl, list or two (C
1-6Alkyl) amino and C
1-6Alkoxy carbonyl; Perhaps
(b) one or more Ar are phenyl or by maximum 3, perhaps by maximum 2, perhaps are selected from the phenyl that following substituting group replaces by one: halogen, hydroxyl, amino, cyano group, C
1-6Alkyl, trifluoromethyl, C
1-6Alkoxyl group, list and two (C
1-6Alkyl) amino; Perhaps
(c) one or more Ar are phenyl or by maximum 3, perhaps by maximum 2, perhaps are selected from the phenyl that following substituting group replaces by maximum 1: halogen, hydroxyl, C
1-6Alkyl, hydroxyl C
1-6Alkyl, trifluoromethyl and C
1-6Alkoxyl group; Perhaps
(d) one or more Ar are phenyl or by maximum 3, perhaps by maximum 2, perhaps are selected from the phenyl that following substituting group replaces by maximum 1: halogen, hydroxyl, C
1-6Alkyl, trifluoromethyl and C
1-6Alkoxyl group; Perhaps
(e) one or more Ar are phenyl or by maximum 3, perhaps by maximum 2, perhaps are selected from the phenyl that following substituting group replaces by maximum 1: halogen, hydroxyl, C
1-6Alkyl and C
1-6Alkoxyl group; Perhaps
(f) one or more Ar are phenyl or by maximum 3, perhaps by maximum 2, perhaps are selected from halogen and C by maximum 1
1-6The phenyl that the substituting group of alkyl replaces.
Certain embodiments of the present invention are (I) compound group or as the subgroup of formula (I) compound that described in detail, wherein R herein
2In contain the Ar group in the last paragraph (a)-(f) detailed description.Certain embodiments of the present invention are (I) compound group or as the subgroup of formula (I) compound that described in detail, wherein R herein
1In Ar in the last paragraph (a)-(f) detailed description.
Formula (I) compound or its any subgroup can be prepared shown in following reaction scheme.
In such scheme, intermediate H-R (III) is
In this scheme, Q, Alk, R
1, R
2, R
3Have above about formula (I) compound or the defined implication of its any subgroup.W is suitable leavings group, and such as tosylate, mesylate or halogen, preferably it is chlorine or bromine.In (III-b), a
1=a
2-a
3=a
4In aromatic nitrogen atom and-CH
2The W partial reaction, thus pyridine _ group formed.The reaction that illustrates in this scheme can be carried out in the presence of alkali in The suitable solvent, described alkali is such as alkaline carbonate, oxyhydroxide or hydride, for example yellow soda ash, salt of wormwood or cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride KH; Perhaps organic bases, such as trialkylamine, triethylamine for example.The suitable solvent that is used for this reaction is that for example, ether is such as THF, two _ alkane; Halohydrocarbon, for example methylene dichloride, CHCl
3Toluene; Polar proton inert solvent is such as DMF, DMSO, DMA or the like.
Formula (I) compound can transform mutually according to functional group known in the art conversion reaction, comprises hereinafter described those reactions.
Cyano group can be reduced to and can carry out alkylating aminomethylene group.The hydroxycarbonyl group group can esterifiedly be C
1-4Alkoxycarbonyl groups, otherwise perhaps, thereby the latter can be hydrolyzed and obtains the former.
Can some functional groups of the intermediate in such scheme or the description intermediate synthetic reaction scheme be protected.Hydroxyl can be protected with benzyl, removes by catalytic hydrogenation subsequently.
The multiple intermediate that is used for preparation formula (I) compound all is the analogue of known compound or known compound, and the modification of the means known in the art that they can obtain easily by those skilled in the art is prepared.Hereinafter, more at large provided the preparation of multiple intermediate.
Formula (II) intermediate can be prepared by the benzoglyoxaline that corresponding formula V hydroxyl methylene radical replaces, by make the latter and suitable leavings group introduce reagent (such as halogenating agent, SOCl for example
2Perhaps POCl
3) reaction, take this hydroxyl methylene group is converted into corresponding halogenated methylene group.Intermediate (V) can be obtained by reduction reaction by corresponding ester (IV), such as using LiAlH
4Carry out reduction reaction.The order of this reaction is carried out illustrations, wherein R by following scheme
aExpression C
1-6Alkyl group is preferably methyl or ethyl.
Intermediate (IV) can obtain as shown in following reaction sequence, wherein R
aAs above illustrated.
In first step, make diaminobenzene (VI) in The suitable solvent (such as dimethylbenzene), carry out cyclisation, thereby obtain benzimidazolone (VII) with urea.Then, be converted into the latter wherein that W is the benzimidizole derivatives (VIII) of aforesaid leavings group, particularly by making (VII) and suitable halogenating agent (POCl for example
3) reaction, and make gained intermediate (VIII) and sulfonamide derivatives (IX) reaction, thus intermediate (X) obtained.The latter is converted into intermediate (IV) by the N-alkylated reaction.
Intermediate (V) can also be prepared by the following method, makes the diaminobenzene of following formula
With cyanogen bromide reaction in The suitable solvent (such as alcohol, for example methyl alcohol or ethanol).
Intermediate (III-a) or (III-b) or compound known or can use the method for institute's illustrations in the following preparation (III-a) to be prepared.Intermediate (III-b) can be prepared with similar method.
(XII) nitro in uses suitable reductive agent (for example using RaneyNi in the presence of hydrogen), reduces in The suitable solvent (such as alcohol, for example methyl alcohol or ethanol).Make gained intermediate (XIII) and C=X introduce reagent react, thereby obtain (XIV).It is urea, thiocarbamide or diimidazole base carbonyl that operable C=X introduces reagent.The suitable solvent that is used for this reaction comprises aromatic hydrocarbon, such as benzene,toluene,xylene; Ether is such as dioxin or THF.
According to well known in the art trivalent nitrogen atom is converted into the method for its N-oxide form, formula (I) compound can be converted into corresponding N-oxide form.Described N-oxidizing reaction can be undertaken by making formula (I) raw material and suitable organic or inorganic peroxide reactions usually.Suitable inorganic peroxide comprises, for example hydrogen peroxide, basic metal or alkaline earth metal peroxide (for example, sodium peroxide, Potassium peroxide); Suitable organo-peroxide can comprise peroxy acid, such as, for example be that benzoyl hydroperoxide or halogen (for example replace benzoyl hydroperoxide (for example, 3-chloroperoxybenzoic acid), peroxide bond alkanoic acid, Peracetic Acid), alkyl peroxide (for example, tertbutyl peroxide).The suitable solvent is, for example the mixture of water, lower alcohol (for example, ethanol or the like), hydro carbons (for example, toluene), ketone (for example, 2-butanone), halohydrocarbon (for example, methylene dichloride) and described solvent.
The pure stereochemistry heterogeneous forms of formula (I) compound can obtain preparation by using methods known in the art.Diastereomer can separate by the physical method such as selective freezing and chromatographic technique, for example counter-current distribution method and liquid chromatography or the like.
Formula (I) compound for preparing in the described method of context is generally the racemic mixture of enantiomer, and they can be separated from each other according to method for splitting well known in the art.By reacting with suitable chiral acid and the chiral base that suits respectively, abundant alkalescence or tart formula (I) racemic compound can be converted into corresponding diastereomer salt form.Subsequently, by for example selective freezing or fractional crystallization described diastereomer salt form is separated, and enantiomer is therefrom separated by alkali or acid.The alternative method of the enantiomerism form of another kind of separate type (I) compound relates to liquid phase chromatography, particularly uses the liquid phase chromatography of chiral stationary phase.Described pure stereochemistry heterogeneous forms can also be derived by the suitable raw material of corresponding pure stereochemistry heterogeneous forms and be obtained, and condition is that described reaction exists stereospecificity.If expectation obtains concrete steric isomer, so preferred described compound synthesizes by stereospecific preparation method.To the advantageously pure raw material of applied optics isomery in these methods.
On the other hand, the present invention relates to pharmaceutical composition, wherein comprise the treatment significant quantity as formula (I) compound that offered some clarification on herein or as the compound and the pharmaceutically acceptable carrier of any subgroup of formula (I) compound that offered some clarification on herein.In context, the treatment significant quantity be enough to prevent, stable or reduce infected object or be in the amount of virus infection of the object of infected danger, and RSV virus infection particularly.Further on the other hand, the present invention relates to prepare the method for the pharmaceutical composition that offers some clarification on as this paper, comprise the pharmaceutically acceptable carrier of thorough mixing and treatment significant quantity as formula (I) compound that this paper offered some clarification on or as the compound of any subgroup of formula (I) compound that this paper offered some clarification on.
Thus, The compounds of this invention or its any subgroup can be mixed with the multiple medicament forms that is used for the administration purpose.Depend on the circumstances, composition can refer to that the system that is generally used for gives all compositions of medicine.In order to prepare pharmaceutical composition of the present invention, particular compound with significant quantity as activeconstituents, optional is additive salt form or metal complexes, be merged into well-mixed mixture with pharmaceutically acceptable carrier, depend on the dosage form of wishing administration, pharmaceutically acceptable carrier can be various ways.These pharmaceutical compositions are eligibly for particularly being suitable for oral administration, rectal administration, percutaneous dosing or through the unit dosage of parenteral injection.For example, in the composition of preparation oral dosage form, any drug media commonly used be can use, for example under the situation of oral liquid (for example suspension, syrup, elixir, emulsion and liquor), water, ethylene glycol, oil and pure or the like for example can be used; Perhaps under the situation of pulvis, pill, capsule and tablet, can use solid carrier, for example starch, sugar, kaolin, lubricant, wedding agent and disintegrating agent or the like.Because be convenient to administration, tablet and capsule are represented best oral dosage unit form, obviously use solid pharmaceutical carriers in the case.For the parenteral composition, described carrier generally includes sterilized water, contains most of sterilized water at least, but also can comprise other composition, so that for example, increases solubleness.For example, can make injectable liquid, wherein carrier comprises the mixture of salt brine solution, glucose solution or salt solution and glucose solution.Injectable suspensions can also be made into, suitable liquid vehicle and suspending agent or the like can be used in this case.Also comprise the solid form preparation that is intended to be converted into soon before use liquid formulation.In being suitable for the composition of percutaneous dosing, optional penetration enhancers and/or the suitable moistening temperature agent of containing of described carrier, optional unite use with the suitable additive than any character of small proportion, described additive can not produce any significant deleterious effect to skin.
The compounds of this invention can also oral administration sucks or is blown into by methods known in the art and this area and is used for carrying out administration through the preparation of this mode administration.Thus, The compounds of this invention usually with the form administration of solution, suspensoid or dry powder to lung, preferred solution.Any exploitation is used for oral administration and sucks or be blown into the system of sending solution, suspensoid or dry powder and all be applicable to and give The compounds of this invention.
Thus, the present invention also provides and has been suitable for wherein comprising formula (I) compound and pharmaceutically acceptable carrier by suck or be blown into the pharmaceutical composition of administration through the oral cavity.The liquor of preferred The compounds of this invention through sucking atomizing or aerosolization dosage carries out administration.
With to make dosage consistent, it is particularly advantageous that aforementioned pharmaceutical compositions is mixed with unit dosage for the ease of administration.The unit dosage of Shi Yonging is meant the physical sepn unit that is suitable for use as unitary dose in this article, and each unit contains the predetermined amount activeconstituents and the needed pharmaceutical carrier that can produce the desired therapeutic effect as calculated.The embodiment of above-mentioned unit dosage is tablet (comprising indentation tablet or sugar coated tablet), capsule, pill, suppository, pulvis bag, plate, injectable liquor or suspensoid or the like, and isolated multiple form.
Formula (I) compound shows antiviral performance.The virus infection that can use The compounds of this invention and method to handle comprise by just with paramyxovirus and the infection that particularly causes by the mankind and bovine respiratory syncytial virus (RSV).In addition, multiple compound of the present invention has activity to the RSV bacterial strain of sudden change.In addition, the multiple compound of the present invention shows favourable pharmacokinetics spectrum and have tempting performance aspect bioavailability, comprise acceptable transformation period, AUC and peak value and do not have unfavorable phenomenon, keep such as inadequate rapid outbreak and tissue.
The compounds of this invention is tested in as the described test of specification sheets test portion the extracorporeal antivirus effect activity of RSV, and has obtained confirmation in virus generation reduction is measured.The compounds of this invention to the interior resisting virus activity of RSV can be in the test model that uses cotton mouse as described in the people such as Wyde (Antiviral Research (1998), 38,31-42) confirm.
Because can being used for the treatment of, their antiviral performance, particularly their anti-RSV performance, formula (I) compound or its any subgroup, additive salt and stereochemistry heterogeneous forms suffer virus infection, particularly rsv infection individual and be used to prevent these infection.Usually, The compounds of this invention can be used for the treatment of the warm-blooded animal that infection has virus, particularly respiratory syncytial virus.
Thus, The compounds of this invention or its any subgroup can be used as medicine.Described as medicine purposes or methods of treatment comprises object that system is infected by the virus or to the significant quantity of object opposing relevant situation with virus infection, particularly rsv infection of virus infection sensitivity.
The invention still further relates to The compounds of this invention or its any subgroup is used for the treatment of or prophylaxis of viral infections in manufacturing, particularly the purposes in the medicine of rsv infection.Described treatment or prevention are carried out in such as the patient group of warm-blooded animal, and be particularly human, children more especially, further more especially the age less than two years old children.Other the patient group who carries out described treatment and prevention is for being in the high risk children of rsv infection, such as the children that suffer from congenital heart defect, bronchopulmonary dysplasia, premature infant with suffer from the baby of immune deficiency disorder; Children or adult that other suffers from chronic long-term disease particularly suffer from the children or the adult of asthma, chronic obstructive pulmonary disease (COPD) or immune deficiency; The elderly or the people in long term care facilities.Other patient group suffers from immune deficiency or is in the patient who is suppressed immunity.The latter comprises the patient who transplants, such as organ transplantation or particularly bone marrow transplantation.
The present invention relates to the method that is infected by the virus or is in the dangerous warm-blooded animal that is infected by the virus for the treatment of in addition, wherein said virus is RSV particularly, described method comprise give antiviral significant quantity as formula (I) compound that this paper offered some clarification on or as the compound of any subgroup of formula (I) compound that this paper offered some clarification on.Described warm-blooded animal comprises any patient group that last paragraph is mentioned.
Usually can expect that antiviral effective per daily dose is 0.01mg/kg～500mg/kg body weight, more preferably 0.1mg/kg～50mg/kg body weight.Among one day, can suitably required dosage be divided into twice, three times, four times or more times sub-doses administration with proper spacing.Described sub-doses can be mixed with unit dosage, for example, each unit dosage contains 1～1000mg activeconstituents, particularly 5～200mg.
Know severity, concrete patient's age, weight, sex, disease degree and general physical condition and the individual other medicines that can take of the situation that the accurate dosage of administration and frequency depend on concrete formula (I) compound of use, the concrete situation for the treatment of, treat as those skilled in the art.In addition, obviously, depend on the response of treatment target and/or depend on the doctor's of format invention compound prescription assessment that described effective per daily dose can reduce or raise.Above Ji Zai effective per daily dose scope only is guiding.
And, other antiviral agent and formula (I) compound compositions can be used as medicine.Thus, the invention still further relates to and contain (a) formula (I) compound and (b) product of other antiviral agent compound, its in antiviral therapy as the combined preparation that is used for simultaneously, separates or order is used.Different medicines can be merged into unitary agent with pharmaceutically acceptable carrier.For example, in order to treat or prevent rsv infection, The compounds of this invention can with interferon-beta or tumor necrosis factor-alpha coupling.
Embodiment
Following examples are used to illustrate the present invention but not it are limited to this.' compound a-6 ', ' compound c-4 ' or the like is meant the same compound in the form to the term of Shi Yonging in these embodiments.
Compound uses following equipment to determine by LC/MS:
LCT: the electrospray ionization of holotype, scan mode are 100～900amu; Xterra MSC18 (Waters, Milford, MA) 5 μ m, 3.9 * 150mm); Flow velocity 1ml/min.Use two kinds of moving phases (mobile phase A: 85%6.5mM ammonium acetate+15% acetonitrile; Mobile phase B: 20%6.5mM ammonium acetate+80% acetonitrile), operation is from 100%A3 minute to 100%B5 minute, 100%B6 minute to 100%A3 minute and use 3 minutes gradient of 100%A balance once more.
ZQ: the electrospray ionization of positive and negative (pulse) pattern, scanning 100～1000amu; XterraRP C18 (Waters, Milford, MA) 5 μ m, 3.9 * 150mm); Flow velocity 1ml/min.Use two kinds of moving phases (mobile phase A: 85%6.5mM ammonium acetate+15% acetonitrile; Mobile phase B: 20%6.5mM ammonium acetate+80% acetonitrile), operation is from 100%A3 minute to 100%B5 minute, 100%B6 minute to 100%A3 minute and use 3 minutes gradient condition of 100%A balance once more.
Embodiment 1
Option A
Ethanol (50ml) mixture of a-1 (0.0083mol) and BrCN (0.0091mol) is stirred and refluxed 1 hour, be cooled to room temperature then and solvent evaporation.The gained resistates is absorbed in CH
2Cl
2In.Gained organic layer 10%K
2CO
3Solution washing, carry out drying (MgSO
4), filter and with solvent evaporation.At CH
3Among the CN resistates (3g) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain 2.2g intermediate a-2 (71%).
Under 0 ℃, with SOCl
2(0.0042mol) be added drop-wise to the CH of a-3 (0.0021mol)
2Cl
2(10ml) in the solution.At room temperature said mixture was stirred 2 hours, evaporate then.The gained resistates is absorbed in the ether.With sedimentation and filtration, carry out drying, obtain 0.99g intermediate a-3 (HCl salt, 100%) with ether washing and to it.
Under 80 ℃, with a-3 (0.0021mol), a-4 (0.0031mol) and Cs
2CO
3DMF (0.0074mol) (20ml) mixture stirred 2 hours, evaporated then.The gained resistates is absorbed in CH
2Cl
2/ CH
3Among the OH.Organic layer 10%K
2CO
3Solution washing, carry out drying (MgSO
4), filter and with solvent evaporation to dry.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (88/11/1); 15-40 μ m) resistates (1.7g) is carried out purifying.Two kinds of cuts are collected and with solvent evaporation, thereby obtained 0.58g intermediate a-5 (51%).
At room temperature with the CH of a-5 (0.0008mol) and Pd/C (0.25g)
3OH (10ml) mixture hydrogenation 6 hours is then with its filtration over celite.Diatomite CH
2Cl
2/ CH
3OH washes.Filtrate is evaporated.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (85/14/1)) resistates (0.4g) is carried out purifying.Pure fraction is collected and with solvent evaporation.In 2-acetone, resistates (0.4g) is carried out crystallization.Precipitation is leached and it is carried out drying.Output: 0.203 final compound a-6 (68%, fusing point: 228 ℃).
Embodiment 2
Option b
Under 5 ℃, with SOCl
2(0.81ml) be added drop-wise to the CH of b-1 (0.0006mol)
2Cl
2(10ml) in the mixture.Under 5 ℃, said mixture was stirred 2 hours, make it be warming up to room temperature then and stirred 12 hours.Solvent evaporation to dry, is obtained 0.42g intermediate b-2 (HCl salt, 100%).
Under 80 ℃, with b-2 (0.0006mol), b-3 (0.0009mol) and K
2CO
3DMF (0.0015mol) (3ml) mixture stirred 4 hours, was poured into H then
2Among the O.Water layer K
2CO
3Powder is saturated, uses ethyl acetate/CH then
3The OH extraction.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (80/20/0.5); 10 μ m) resistates (0.5g) is carried out purifying.Pure fraction is collected and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (80/20/1.5); 10 μ m) resistates (0.5g) is carried out purifying.Pure fraction is collected and with solvent evaporation.At CH
3CN/CH
3Among the OH gained resistates (0.1g) is carried out crystallization.Gained precipitation is leached and it is carried out drying.Output: 0.06g final compound b-4 (7%, fusing point: 227 ℃).
Embodiment 3
Scheme C
Under 0 ℃, with SOCl
2(0.0018mol) join the CH of c-1 (0.0003mol)
2Cl
2(20ml) in the mixture.Under 5 ℃, said mixture was stirred 2 hours, at room temperature stirred then 12 hours.Solvent evaporation is extremely dry.Resistates is absorbed in the Di Iso Propyl Ether.With the mixture evaporation, obtain: 0.21g intermediate c-2 (HCl salt, 100%).
Under 80 ℃, with c-2 (0.0006mol), c-3 (0.0009mol) and K
2CO
3DMF (0.0015mol) (3ml) mixture stirred 4 hours, poured into H
2Among the O, use K
2CO
3Powder is saturated and with ethyl acetate/CH
3OH (on a small quantity) extracts.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (85/15/1.5); 10 μ m) gained resistates (0.6g) is carried out purifying.Pure fraction is collected and with solvent evaporation.Output: 0.1g.At CH
3CN/CH
3Among the OH this fraction is carried out crystallization.Precipitation is leached and it is carried out drying.Output: 0.045g final compound c-4 (3%, fusing point: 175 ℃).
Embodiment 4
Scheme D
Under 3bar pressure, at room temperature with the CH of d-1 (0.0022mol) and Raney nickel (0.2g)
3OH (40ml) mixture hydrogenation 1 hour is then with its filtration over celite.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation to dry.Output: 0.33g intermediate d-2 (100%).
Dimethylbenzene (20ml) mixture of d-2 (0.0012mol) and urea (0.0026mol) is stirred and refluxed 12 hours, then it is cooled to room temperature.With precipitation leach, with Di Iso Propyl Ether washing and carry out drying.Output: 0.34g intermediate d-3 (87%, fusing point: 197 ℃).
Under 80 ℃, with d-4 (0.0003mol), d-3 (0.0003mol) and Cs
2CO
3DMF (0.0017mol) (20ml) mixture stirred 4 hours, was poured in the frozen water then and used CH
2Cl
2Extraction.Water layer K
2CO
3Saturated, use CH then
2Cl
2/ CH
3OH (95/5) extraction.The organic layer that is combined carries out drying (MgSO
4), filter and with solvent evaporation to dry.In the 2-acetone, the gained resistates is carried out crystallization.Precipitation is leached and carry out drying, obtain 0.095g final compound d-5 (48%, fusing point: 243 ℃).
Embodiment 5
Scheme E
Under 60 ℃, the mixture of e-1 (0.0037mol) and e-2 (0.0151mol) was stirred 2 hours, then on silica gel by column chromatography (elutriant: CH
2Cl
2/ CH
3OH (98/2); 15 μ m) carry out purifying.Pure fraction is collected and with solvent evaporation.Output: 1g intermediate e-3 (100%).
Under 3bar pressure, at room temperature with the CH of a-3 (0.0036mol) and Raney nickel (1g)
3OH (30ml) mixture hydrogenation 30 minutes is then with its filtration over celite.Diatomite CH
3OH washes.Filtrate is evaporated.Output: 0.3g intermediate e-4 (34%).
Dimethylbenzene (10ml) mixture of e-4 (0.0006mol) and urea (0.0007mol) is stirred and refluxed 12 hours, then it is cooled to room temperature.Precipitation is leached and it is carried out drying.Output: 0.1g intermediate e-5 (62%).
Under 80 ℃, with e-6 (0.0006mol), e-5 (0.0006mol) and K
2CO
3DMF (0.003mol) (20ml) mixture stirred 4 hours, poured in the frozen water, used K
2CO
3Powder is saturated and use CH
2Cl
2And CH
3OH extracts.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation to dry.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (90/10/0.5); 15 μ m) the gained resistates is carried out purifying.Pure fraction is collected and with solvent evaporation.At 2-acetone/CH
3In the CN/ Di Iso Propyl Ether resistates (0.12g, 30%) is carried out crystallization.Precipitation is leached and it is carried out drying.Output: 0.03g final Verbindung-7 (13%, fusing point: 173 ℃).
Embodiment 6
Scheme F
Under 1.5bar pressure, at room temperature with the CH of f-1 (0.0148mol), Raney nickel (3g) and thiophene (0.1ml)
3OH (50ml) mixture hydrogenation 1 hour is then with its filtration over celite.Diatomite CH
3OH washes.With the filtrate evaporation, obtain 2.8g intermediate f-2 (100%).
At room temperature, THF (25ml) mixture with f-2 (0.0132mol) and f-3 (0.0132mol) stirred 2 hours.With solvent evaporation.Resistates is absorbed in CH
2Cl
2In and use H
2O washs.Organic layer is carried out drying (MgSO
4), filter and concentrate.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (96/4/0.2); 15-40 μ m) gained resistates (3.5g) is carried out purifying.Pure fraction is collected and with solvent evaporation, thereby obtained 1.04g intermediate f-4 (39%).
Under 0 ℃, at N
2In the stream, 60% oil solution (0.00205mol) of NaH is added drop-wise in THF (3ml) solution of f-4 (0.00205mol).Under this temperature, will react and stir 30 minutes, then f-5 be added wherein.At room temperature, at N
2To react in the stream and stir 1.5 hours, make its hydrolysis with ice very carefully then.Gained solution K
2CO
3The saturated ethyl acetate extraction of using then of powder.Organic layer is carried out drying (MgSO
4), filter and concentrate.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (90/10/0.5)) resistates (0.7g) is carried out purifying.Pure fraction is collected and with solvent evaporation.The final compound f-6 of output: 0.036g (9%, fusing point＞250 ℃).
Embodiment 7
Scheme G
Ethanol (10ml) mixture of g-1 (0.0078mol) and g-2 (0.0094mol) is stirred and refluxed 24 hours, it is cooled to 0 ℃ then.With precipitation leach, with washing with alcohol and carry out drying, thereby obtain 1.8g intermediate g-3 (88%, fusing point: 154 ℃).
Under 3bar pressure, with methyl alcohol (50ml) the mixture hydrogenation of g-3 (0.068mol) and Raney nickel (1.8g) 1 hour, then with its filtration over celite pad.Under reduced pressure gained filtrate is concentrated, thereby obtain 1.8g intermediate g-4 (100%).
Under 160 ℃, dimethylbenzene (10ml) mixture of g-4 (0.0084mol) and urea (0.01mol) was stirred 6 hours, then it is cooled to room temperature, topple in the entry and use CH
2Cl
2Extract.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.At CH
3Among the CN resistates (1.5g) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain 0.67g intermediate g-5 (31%, fusing point: 169 ℃).
Under 80 ℃, with g-6 (0.0011mol), g-5 (0.0011mol) and K
2CO
3DMF (0.0046mol) (5ml) mixture stirred 2 hours, was poured into then in the water (minute quantity).With CH
2Cl
2Add wherein.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (90/10/1); 5 μ m) gained resistates (0.4g) is carried out purifying.Pure fraction is collected and with solvent evaporation.In 2-acetone, resistates (0.13g) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound g-7 of 0.062g (21%, fusing point: 245 ℃).
Embodiment 8
Scheme H
Under 160 ℃, dimethylbenzene (10ml) mixture of h-1 (0.0078mol) and urea (0.0094mol) was stirred 6 hours, then it is cooled to room temperature, topple in the entry and use CH
2Cl
2Extract.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.At CH
3Among the CN gained resistates (3.5g) is carried out crystallization.Precipitation is leached and it is carried out drying.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (95/5/0.5)) mother liquid obtained layer is carried out purifying.Pure fraction is collected and with solvent evaporation, thereby obtained 0.75g intermediate h-2 (38%).
Under 80 ℃, with h-3 (0.0003mol), h-2 (0.0005mol) and Cs
2CO
3DMF (0.0017mol) (3ml) mixture stirred 2 hours, under reduced pressure it was concentrated then.Resistates is absorbed in ethyl acetate/CH
3Among the OH.The saturated K of organic layer
2CO
3The aqueous solution (10mL) washs, carries out drying (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (88/12/1.2); 5 μ m) gained resistates (0.25g) is carried out purifying.Pure fraction is collected and with solvent evaporation, thereby obtained the final compound h-4 of 0.028g (12%, fusing point: 187 ℃).
Embodiment 9
Scheme I
Under 80 ℃, with i-1 (0.0003mol), i-2 (0.0004mol) and Cs
2CO
3DMF (0.0017mol) (3ml) mixture stirred 2 hours, under reduced pressure it was concentrated then.Resistates is absorbed in ethyl acetate/CH
3Among the OH.The saturated K of gained organic layer
2CO
3Solution washing, carry out drying (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (87/17/1.7); 5 μ m) gained resistates (0.4g) is carried out purifying.Pure fraction is collected and with solvent evaporation.Be dissolved in gained resistates (0.083g) in the HCl/2-propyl alcohol and be translated into hydrochloride.Precipitation is leached and it is carried out drying, thereby obtain 0.065g final compound i-3 (HCl salt, 22%, fusing point: 180 ℃).
Embodiment 10
Scheme J
Under 160 ℃, dimethylbenzene (10ml) mixture of j-1 (0.0086mol) and urea (0.0103mol) was stirred 5 hours, then it is cooled to room temperature, topple in the entry and use CH
2Cl
2Extract.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.At CH
3Among the CN (minute quantity) resistates (2g) is carried out crystallization.Precipitation is leached and it is carried out drying.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH (90/10/0.5) carries out purifying to resistates (0.4g).Pure fraction is collected and with solvent evaporation, thereby obtained 0.5g intermediate j-2 (59%, fusing point: 134 ℃).
With K
2CO
3(0.0047mol) join in DMF (5ml) mixture of j-3 (0.0011mol) and j-2 (0.0014mol).Under 80 ℃, said mixture was stirred 2 hours, under reduced pressure it is concentrated then.Resistates is absorbed in CH
2Cl
2/ CH
3Among the OH.The saturated K of organic layer
2CO
3Solution washing, carry out drying (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 90/10/1; 5 μ m) resistates (0.7g) is carried out purifying.Pure fraction is collected and with solvent evaporation.In 2-acetone, resistates (0.2g) is carried out crystallization.Precipitation is leached and it is carried out drying, output: the final compound j-4 of 0.136g (38%, fusing point: 250 ℃).
Embodiment 11
Scheme K
Under 0 ℃, at N
2In the stream NaH (0.0011mol) is joined in THF (5ml) solution of k-2 (0.0011mol).Under 5 ℃, said mixture was stirred 30 minutes.K-1 (0.0003mol) is added wherein.At room temperature, at N
2In the stream said mixture was stirred 1.5 hours.Reaction mixture is slowly poured in the ice, uses K
2CO
3Saturated and use ethyl acetate extraction.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 97/3/0.3～86/14/1.4; 5 μ m) gained resistates (0.3g) is carried out purifying.Pure fraction is collected and with solvent evaporation, thereby obtained the 0.019g product.In 2-acetone/Di Iso Propyl Ether, the gained resistates is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound k-3 of 0.017g (8%, fusing point: 120 ℃).
Embodiment 12
Scheme L
Under 0 ℃, at N
2In the stream NaH (0.0018mol) is joined in THF (10ml) solution of 1-2 (0.0018mol).Under 5 ℃, said mixture was stirred 30 minutes.1-1 (0.0006mol) is added wherein.At room temperature, at N
2In the stream said mixture was stirred 1.5 hours, it is slowly poured in the ice, uses K
2CO
3Saturated and use ethyl acetate extraction.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 96/4/0.3～87/13/1.3; 5 μ m) resistates (0.67g) is carried out purifying.Pure fraction is collected and with solvent evaporation.In 2-acetone/Di Iso Propyl Ether, resistates is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound 1-3 of 0.036g (10%, fusing point: 198 ℃).
According to identical method, prepare the compound 1-4 in being listed in the table below.
Embodiment 13
Scheme M
Under 125 ℃, the mixture of m-1 (0.0273mol) and m-2 (0.1095mol) was stirred 5 hours, be poured into 10%K then
2CO
3In the solution.Solution K
2CO
3(powder) is saturated, and uses CH
2Cl
2/ CH
3The OH extraction.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 88/12/0.5; 20-45 μ m) resistates (16g) is carried out purifying.Pure fraction is collected and with solvent evaporation, thereby obtained 5.4g intermediate m-3 (71%, fusing point: 173 ℃).
At room temperature, with m-3 (0.0098mol), m-4 (0.0117mol) and K
2CO
3DMF (0.03mol) (30ml) mixture stirred 12 hours, stirred 3 hours down at 60 ℃, was poured in the frozen water then.Solution K
2CO
3Saturated, and use CH
2Cl
2/ CH
3The OH extraction.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 85/14/1; 15-40 μ m) resistates (5.2g) is carried out purifying.Two cuts are collected and with solvent evaporation, thereby obtained 1.36g F1 (35%) and 1.51g F2 (39%).In 2-acetone, F1 is carried out crystallization.Precipitation is leached and it is carried out drying, output: 1.2g intermediate m-5 (31%, fusing point: 190 ℃).At 2-acetone/CH
3Among the OH F2 is carried out crystallization.Precipitation is leached and it is carried out drying, output: 1.2g intermediate m-6 (31%, fusing point: 230 ℃).
Under 5 ℃, with SOCl
2(0.0019mol) be added drop-wise to the CH of m-5 (0.0003mol)
2Cl
2(20ml) in the solution.Under 5 ℃, said mixture was stirred 2 hours, at room temperature stirred 12 hours, under reduced pressure it is concentrated then, obtain intermediate m-7 (100%).
Under 80 ℃, with m-7 (0.0003mol), m-8 (0.0005mol) and K
2CO
3DMF (0.0011mol) (20ml) mixture stirred 4 hours, was poured in the ice then.Solution K
2CO
3Saturated, and use CH
2Cl
2/ CH
3The OH extraction.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 92/8/0.8～80/20/2; 5 μ m) resistates (0.35g) is carried out purifying.Pure fraction is collected and with solvent evaporation.At CH
3In the OH/ Di Iso Propyl Ether resistates (0.115g) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound m-9 of 0.089g (43%, fusing point: 204 ℃).
Embodiment 14
Scheme N
At room temperature, with m-3 (0.0098mol), m-4 (0.0117mol) and K
2CO
3DMF (0.03mol) (30ml) mixture stirred 12 hours, stirred 3 hours down at 60 ℃, was poured in the frozen water then.With K
2CO
3Add wherein, and solution CH
2Cl
2/ CH
3The OH extraction.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 88/12/1; 15-40 μ m) gained resistates (5g) is carried out purifying.Collect two kinds of cuts and, obtain 1g intermediate n-3 (27%, 227 ℃ of fusing points) and 1.1g intermediate n-4 (29%, 195 ℃ of fusing points) solvent evaporation.
Under 5 ℃, with SOCl
2(0.0022mol) be added drop-wise to the CH of n-3 (0.0004mol)
2Cl
2(10ml) in the solution.Under 5 ℃, said mixture was stirred 1 hour, at room temperature stir 12 hours, and under reduced pressure it is concentrated.The gained resistates is absorbed in the Di Iso Propyl Ether.Gained precipitation is leached and it is carried out drying, thereby obtain 0.215g intermediate n-5 (88%).
Under 80 ℃, with n-5 (0.0003mol), n-6 (0.0005mol) and K
2CO
3DMF (0.0011mol) (7ml) mixture stirred 5 hours, was poured in the water then.Gained water layer K
2CO
3(powder) is saturated.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH93/7/0.7～80/20/2; 5 μ m) gained resistates (0.4g) is carried out purifying.Pure fraction is collected and with solvent evaporation.At CH
3In the OH/ Di Iso Propyl Ether gained resistates is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound n-7 of 0.016g (8%, fusing point: 184 ℃).
Embodiment 15
Scheme O
Under 80 ℃, with o-1 (0.0005mol), o-2 (0.0005mol) and Cs
2CO
3DMF (0.0026mol) (5ml) mixture stirred 2 hours, under reduced pressure it was concentrated then.The gained resistates is absorbed in ethyl acetate and CH
3Among the OH.The saturated K of gained organic layer
2CO
3Solution washing, carry out drying (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 88/12/1.2; 5 μ m) resistates (0.5g) is carried out purifying.Pure fraction is collected and with solvent evaporation.Be dissolved in resistates (0.054g) in the Virahol and be translated into hydrochloride.Precipitation is leached and it is carried out drying, output: the final compound o-3 of 0.03g (16%, fusing point: 170 ℃).
Embodiment 16
Scheme P
Under 80 ℃, with p-1 (0.0005mol), p-2 (0.0007mol) and Cs
2CO
3DMF (0.0026mol) (5ml) mixture stirred 2 hours, was poured in the water then.With CH
2Cl
2Add wherein.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 90/10/1; 5 μ m) resistates (0.5g) is carried out purifying.Pure fraction is collected and with solvent evaporation.At 2-acetone/CH
3In the OH/ ether resistates (0.15g) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound p-3 of 0.084g (45%, fusing point: 230 ℃).
Embodiment 17
Scheme Q
With K
2CO
3(0.0047mol) join in DMF (5ml) mixture of q-1 (0.0011mol) and q-2 (0.0014mol).Under 80 ℃, said mixture was stirred 2 hours, under reduced pressure it is concentrated then.Resistates is absorbed in CH
2Cl
2/ CH
3Among the OH.The saturated K of organic layer
2CO
3Solution washing, carry out drying (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 90/10/1; 15-40 μ m) resistates (1g) is carried out purifying.Pure fraction is collected and with solvent evaporation.In 2-acetone, gained resistates (0.275g) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound q-3 of 0.158g (45%, fusing point: 238 ℃).
Embodiment 18
Scheme R
Under 5 ℃, with SOCl
2(0.003mol) join the CH of r-2 (0.0006mol)
2Cl
2(25ml) in the solution.Under 5 ℃, said mixture was stirred 2 hours, at room temperature stirred 12 hours, under reduced pressure it is concentrated then, obtain intermediate r-2 (100%).
Under 80 ℃, with r-2 (0.0006mol), r-3 (0.0009mol) and K
2CO
3DMF (0.0018mol) (30ml) mixture stirred 5 hours, poured in the frozen water, used K
2CO
3Saturated and use CH
2Cl
2/ CH
3OH extracts.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 85/15/1.5～80/20/2; 10 μ m) resistates (0.5g) is carried out purifying.Pure fraction is collected and with solvent evaporation.At 2-acetone/CH
3Among the OH resistates (0.12g, 35%) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound r-4 of 0.08g (23%, fusing point: 201 ℃).
Embodiment 19
Scheme S
At room temperature, CDI (0.04mol) is joined in THF (100ml) solution of s-1 (0.04mol).At room temperature said mixture was stirred 3 hours, under reduced pressure it is concentrated then.Resistates is absorbed in CH
2Cl
2/ H
2Among the O.Mixture CH
2Cl
2Extract.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.With CH
3CN adds wherein.Precipitation is leached and it is carried out drying, thereby obtain 4.6g intermediate s-2 (46%).
Under 0 ℃, at N
2In the stream NaH (0.0024mol) is joined in THF (15ml) solution of s-2 (0.0024mol).Under 5 ℃, said mixture was stirred 30 minutes.S-3 (0.0008mol) is added wherein.At room temperature, at N
2In the stream said mixture was stirred 1 hour 30 minutes, slowly pour in the ice.Gained solution K
2CO
3The saturated ethyl acetate extraction of using then.With organic layer separation, dry (MgSO
4), filter and with solvent evaporation.On silica gel, pass through column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 98/2/0.2～91/9/0.9; 5 μ m) gained resistates (0.91g) is carried out purifying.Pure fraction is collected and with solvent evaporation.In 2-acetone, gained resistates (0.057g) is carried out crystallization.Precipitation is leached and it is carried out drying, thereby obtain the final compound s-4 of 0.05g (10%, fusing point: 196 ℃).
The listed compound of following table is prepared according to any one the foregoing description.
Table 1
Dotted line in the last table represents that this group is connected the key on the molecule remainder.
Table 2
Table 3
Dotted line in the last table represents that group is connected the key on the molecule remainder.
Embodiment 20: to the active in-vitro screening of respiratory syncytial virus
Cytopathology prevention per-cent (antiviral activity or the EC that virus is caused that realize by test compounds
50) and their cytotoxicity (CC
50) all calculate by dose response curve.The selectivity of antivirus action is by selectivity index (SI) expression, and this index passes through CC
50(to the cytotoxicity dosage of 50% cell) is divided by EC
50(to the antiviral activity of 50% cell) calculates.
Be used to measure the EC of test compounds automatically based on the colorimetric analysis of tetrazolium
50And CC
50Flat 96-hole plastic microtiter is filled with 180 μ lEagle ' s basic medium, is supplemented with 5% foetal calf serum (FCS) and 20mM Hepes damping fluid.Subsequently, in the three parts of hole series of compound mother liquor (7.8 * final trial concentration) adding with 45 μ l volumes, thereby can estimate their effects simultaneously to virus infected cell and simulated infection cell.In the microtiter plate system, use automatic control system directly to prepare five parts of 5 times of dilutions.Untreated virus control and the contrast of HeLa cell are joined in each time test.With 50 μ l volumes with about 100TCID
50Respiratory syncytial virus join three row in two row in.The substratum of equal volume is joined among the 3rd row, thereby be determined at the cytotoxicity of the compound under the same concentrations that is used to measure antiviral activity.After cultivating in two hours, with HeLa cell suspending liquid (4 * 10
5Cell/ml) with the volume of 50 μ l join institute porose in.At 5%CO
2Under the atmosphere, under 37 ℃, culture is cultivated.After infecting seven days, pair cell toxicity and antiviral activity carry out spectrophotometric determination.In each hole of microtiter plate, add 25 μ lMTT (3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene bromination tetrazolium) solution.Under 37 ℃, flat board was further cultivated 2 hours, after this substratum is removed from each cup.By adding 100 μ l 2-propyl alcohol, first _ crystalline solvency action can be accomplished.Flat board is being placed oscillator plate after last 10 minute, first _ crystalline dissolves accomplished fully.At last, under two kinds of wavelength (540 and 690nm), go up at the photometer (Multiskan MCC, Flow Laboratories) of eight channel computers control absorbancy is carried out reading.The absorbancy that to measure under 690nm deducts the absorbancy of measuring automatically under 540nm, thereby eliminates non-specific sorption.
Claims (12)
1. the compound that has following formula
Its salt or stereochemistry heterogeneous forms, wherein R is the group of following formula
Q is hydrogen or optional heterocyclically substituted C
1-6Alkyl, perhaps Q is by group-OR
4C with heterocyclic substituted
1-6Alkyl; Wherein said heterocycle is selected from _ azoles alkane, thiazolidine, 1-oxo-thiazolidine, 1,1-dioxo thiazolidine, morpholinyl, thio-morpholinyl, 1-oxo-thio-morpholinyl, 1, the assorted azepine of 1-dioxo thio-morpholinyl, six hydrogen-oxygens _, six hydrogen thia azepines _, 1-oxo-six hydrogen thia azepine _, 1,1-dioxo-six hydrogen thia azepine _, tetramethyleneimine, piperidines, high piperidines, piperazine; Wherein said heterocycle can be chosen wantonly separately by one or two and be selected from following substituting group replacement: C
1-6Alkyl, hydroxyl C
1-6Alkyl, aminocarboxyl C
1-6Alkyl, hydroxyl, carboxyl, C
1-6Alkoxy carbonyl, aminocarboxyl, list or two (C
1-6Alkyl) aminocarboxyl, C
1-6Alkyl-carbonyl-amino, amino-sulfonyl and single or two (C
1-6Alkyl) amino-sulfonyl;
Alk is C
1-6Alkylidene group;
X is O or S;
-a
1=a
2-a
3=a
4-be formula-N=CH-CH=CH-,-CH=N-CH=CH-,-CH=CH-N=CH-or-divalent group of CH=CH-CH=N-; One of them nitrogen-atoms has the chemical bond of linking group (b) and molecule remainder;
R
1For Ar or be selected from following heterocycle: pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, tetrahydrofuran base, thienyl, pyrryl, thiazolyl, _ azoles base, imidazolyl, isothiazolyl, pyrazolyl, different _ the azoles base, _ di azoly, quinolyl, quinoxalinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo _ azoles base, benzothiazolyl, the pyridopyridine base, naphthyridinyl, 1H-imidazo [4,5-b] pyridyl, 3H-imidazo [4,5-b] pyridyl, imidazo [1,2-a] pyridyl and 2,3-dihydro-1,4-two _ alkene is [2,3-b] pyridyl also; Wherein each described heterocycle can be chosen wantonly by 1,2 or 3 and be selected from following substituting group replacement independently of one another: halogen, hydroxyl, amino, cyano group, carboxyl, C
1-6Alkyl, C
1-6Alkoxyl group, hydroxyl C
1-6Alkoxyl group, (C
1-6Alkyl-oxygen base) C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkoxy C
1-6Alkyl, hydroxyl C
1-6Alkyl, list or two (C
1-6Alkyl) amino, single or two (C
1-6Alkyl) amino C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6Alkyl-carbonyl-amino, C
1-6Alkoxy carbonyl, aminocarboxyl, list and two-C
1-6Alkyl amino-carbonyl;
R
2Be hydrogen, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, Ar-C
1-6Alkoxy C
1-6Alkyl, C
3-7Cycloalkyl, cyano group-C
1-6Alkyl, Ar-C
1-6Alkyl, Het-C
1-6Alkyl;
R
3Be hydrogen, C
1-6Alkyl, cyano group, aminocarboxyl, many halos C
1-6Alkyl, C
2-6Thiazolinyl or C
2-6Alkynyl;
R
4Be hydrogen or C
1-6Alkyl;
Ar is phenyl or by 1～5 independently of one another, is selected from the phenyl that following substituting group replaces such as 1,2,3 or 4: halogen, hydroxyl, amino, list or two (C
1-6Alkyl) amino, C
1-6Alkyl-carbonyl-amino, C
1-6Alkyl sulfonyl-amino, cyano group, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, phenyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, amino C
1-6Alkyl, list or two (C
1-6Alkyl) amino C
1-6Alkyl, C
1-6Alkoxyl group, many halos C
1-6Alkoxyl group, phenoxy group, aminocarboxyl, list or two (C
1-6Alkyl) aminocarboxyl, hydroxycarbonyl group, C
1-6Alkoxy carbonyl, C
1-6Alkyl-carbonyl, amino-sulfonyl, list and two (C
1-6Alkyl) amino-sulfonyl;
Het is selected from following heterocycle: pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, tetrahydrofuran base, thienyl, pyrryl, thiazolyl, _ azoles base, imidazolyl, isothiazolyl, pyrazolyl, different _ the azoles base, _ di azoly, quinolyl, quinoxalinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo _ azoles base, benzothiazolyl, the pyridopyridine base, naphthyridinyl, 1H-imidazo [4,5-b] pyridyl, 3H-imidazo [4,5-b] pyridyl, imidazo [1,2-a] pyridyl and 2,3-dihydro-1,4-two _ alkene is [2,3-b] pyridyl also; Wherein Het can choose wantonly separately by 1,2 or 3 and be selected from halogen, hydroxyl, amino, list or two (C independently of one another
1-6Alkyl) amino, cyano group, C
1-6Alkyl, hydroxyl C
1-6Alkyl, many halos C
1-6Alkyl, C
1-6The substituting group of alkoxyl group replaces.
2. according to the compound of claim 1, wherein compound has formula (I-a-1):
Wherein Q, R
1, Alk and R
2And R
3As defined in claim 1.
3. according to the compound of claim 1, wherein compound has formula (I-a-2):
Wherein Q, R
1, Alk and R
2As defined in claim 1.
4. according to the compound of claim 1-3, R wherein
1For being independently selected from hydroxyl, C by 1 or 2
1-6Alkyl, halogen, C
1-6Alkoxyl group and (C
1-6Alkoxyl group) C
1-6The pyridyl that the substituting group of alkoxyl group replaces.
5. according to each compound of claim 1-4, wherein Alk is a methylene radical.
6. according to each compound of claim 1-5, wherein R
2Be C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, C
3-7Cycloalkyl, cyano group-C
1-6Alkyl.
7. according to each compound of claim 1-6, wherein R
3Be hydrogen.
8. according to each compound of claim 1-7, wherein R
4Be hydrogen.
9. according to each compound of claim 1-8, the C of Q wherein for being replaced by morpholinyl
1-6Alkyl.
10. according to each compound of claim 1-9, it is as medicine.
11. a pharmaceutical composition, wherein contain pharmaceutically acceptable carrier and as the treatment significant quantity of activeconstituents as each compound of claim 1～9.
12. a method for preparing as each defined compound among the claim 1-9 wherein makes benzimidizole derivatives (II) and reagent (III) reaction:
Wherein Q, Alk, R
1Have the implication that defines among the claim 1-9, and W represents leavings group;
And optional by making alkali form and suitable acid-respons, when perhaps suitable and alkali reaction, the salt form of preparation formula (I) compound.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05076438 | 2005-06-20 | ||
| EP05076438.0 | 2005-06-20 | ||
| PCT/EP2006/063365 WO2006136561A1 (en) | 2005-06-20 | 2006-06-20 | 1- ( 2-amino-3- (substituted alkyl)-3h-benzimidazoiylmethyl) -3-subtituted-1,3-dihydro-benzoimidazol-2-ones with activity on respiratory syncytial virus |
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| CN101203517A true CN101203517A (en) | 2008-06-18 |
| CN101203517B CN101203517B (en) | 2011-07-06 |
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| Country | Link |
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| US (1) | US8034835B2 (en) |
| EP (1) | EP1896473B1 (en) |
| JP (1) | JP5078887B2 (en) |
| CN (1) | CN101203517B (en) |
| AT (1) | ATE529424T1 (en) |
| AU (1) | AU2006260969B2 (en) |
| BR (1) | BRPI0612628B8 (en) |
| CA (1) | CA2612263C (en) |
| MX (1) | MX2007016537A (en) |
| RU (1) | RU2434000C2 (en) |
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| JP2009525269A (en) | 2006-01-30 | 2009-07-09 | ユーロ−セルティーク エス．エイ． | Cyclic urea compounds as calcium channel blockers |
| KR102066297B1 (en) | 2011-10-14 | 2020-01-14 | 암비트 바이오사이언시즈 코포레이션 | Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases |
| SG11201600977XA (en) | 2013-08-21 | 2016-03-30 | Alios Biopharma Inc | Antiviral compounds |
| MA41614A (en) | 2015-02-25 | 2018-01-02 | Alios Biopharma Inc | ANTIVIRAL COMPOUNDS |
| JO3637B1 (en) * | 2015-04-28 | 2020-08-27 | Janssen Sciences Ireland Uc | Rsv antiviral pyrazolo- and triazolo-pyrimidine compounds |
| CA3077309A1 (en) | 2017-09-29 | 2019-04-04 | Enanta Pharmaceuticals, Inc. | Combination pharmaceutical agents as rsv inhibitors |
| TW201932470A (en) | 2017-11-29 | 2019-08-16 | 愛爾蘭商健生科學愛爾蘭無限公司 | Pyrazolopyrimidines having activity against RSV |
| CA3087926A1 (en) | 2018-01-31 | 2019-08-08 | Janssen Sciences Ireland Unlimited Company | Cycloalkyl substituted pyrazolopyrimidines having activity against rsv |
| KR20210005569A (en) | 2018-04-23 | 2021-01-14 | 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 | Heteroaromatic compounds having activity against RSV |
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| JP2003503403A (en) * | 1999-06-28 | 2003-01-28 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Respiratory syncytial virus replication inhibitor |
| TR200103806T2 (en) | 1999-06-28 | 2002-06-21 | Janssen Pharmaceutica N. V. | Substances that inhibit the replication of the respiratory syncytial virus. |
| DE60013836T2 (en) | 1999-06-28 | 2006-01-19 | Janssen Pharmaceutica N.V. | REPLICATION INHIBITORS OF RESPIRATORY SYNZYTIAL VIRUS |
| US6489338B2 (en) | 2000-06-13 | 2002-12-03 | Bristol-Myers Squibb Company | Imidazopyridine and imidazopyrimidine antiviral agents |
| US8044073B2 (en) * | 2003-12-18 | 2011-10-25 | Tibotec Pharmaceuticals | Aminobenzimidazoles and benzimidazoles as inhibitors of respiratory syncytial virus replication |
| AR046959A1 (en) * | 2003-12-18 | 2006-01-04 | Tibotec Pharm Ltd | MORFOLINILO CONTAINING BENCIMIDAZOLS AS INHIBITORS OF THE REPLICATION OF RESPIRATORY SYNTHETIC VIRUSES |
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| Publication number | Publication date |
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| ZA200711080B (en) | 2009-03-25 |
| AU2006260969A1 (en) | 2006-12-28 |
| WO2006136561A1 (en) | 2006-12-28 |
| RU2008102057A (en) | 2009-07-27 |
| BRPI0612628A2 (en) | 2012-01-03 |
| AU2006260969B2 (en) | 2011-11-17 |
| CA2612263C (en) | 2015-04-14 |
| JP5078887B2 (en) | 2012-11-21 |
| MX2007016537A (en) | 2008-03-06 |
| CN101203517B (en) | 2011-07-06 |
| BRPI0612628B8 (en) | 2021-05-25 |
| JP2008546738A (en) | 2008-12-25 |
| RU2434000C2 (en) | 2011-11-20 |
| CA2612263A1 (en) | 2006-12-28 |
| EP1896473A1 (en) | 2008-03-12 |
| BRPI0612628B1 (en) | 2019-12-03 |
| US8034835B2 (en) | 2011-10-11 |
| US20100183552A1 (en) | 2010-07-22 |
| ATE529424T1 (en) | 2011-11-15 |
| EP1896473B1 (en) | 2011-10-19 |
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